Anaplastic lymphoma kinase (ALK) protein is a member of the insulin receptor superfamily of receptor tyrosine kinases. ALK is a type I membrane glycoprotein that is normally expressed only in the nervous system. An inversion within chromosome 2p, resulting in the formation of a fusion gene product comprising portions of the echinoderm microtubule associated protein-like 4 (EML4) gene and the ALK gene, was discovered in non-small cell lung carcinoma (NSCLC) cell lines and archived clinical specimens (Soda et al., Nature 448:561-566, 2007). ALK is now recognized as a critical player in NSCLC, and although EML4 is the predominant fusion partner, other fusion partner genes have been identified. The incidence of ALK gene rearrangements appears to range from 2-7%, translating to about 6,000 ALK positive patients/year in the United States and about 40,000 patients/year worldwide. Importantly, ALK gene rearrangements are rarely coincident with EGFR, HER2, or KRAS mutations, demonstrating that ALK positivity is a distinct disease subtype.
Crizotinib (XALKORI, Pfizer) is a potent receptor tyrosine kinase inhibitor that inhibits ALK. In two clinical trials, ALK-positive locally advanced or metastatic NSCLC patients who were treated with crizotinib exhibited overall response rates of 50% (N=136; 95% CI: 42%, 59%) and 61% (N=119; 95% CI: 52%, 70%), respectively. Thus, determination of ALK status in NSCLC patients is critical for directing patient care. However, there remains a need for a specific, sensitive, and standardized assay for ALK status to quickly and accurately identify NSCLC patients most likely to be responsive to crizotinib treatment.